Project 1 addresses the regulation of keratinocyte differentiation and inflammation and the relationship of these processes to cutaneous cancer initiation. We show that CLIC4, a p53 and c-Myc inducible chloride channel protein, is required for keratinocyte differentiation. During keratinocytes differentiation cytoplasmic CLIC4 translocates to the nucleus through a process involving cysteine nitrosylation, and nuclear CLIC4 induces the expression of differentiation markers. In a second approach we show that protein kinase C (PKC) alpha mediates keratinocyte intraepidermal neutrophilic infiltration through upregulation of ligands for CXCR2, and that receptor on keratinocytes is required for tumor growth. Furthermore, there is synergy between the EGF receptor and cytokines for induction of GM-CSF, a cytokine involved in cutaneous inflammation. Cutaneous inflammation is also mediated by upregulation of S100A15, an EF hand protein that is particularly elevated in psoriasis and certain human cancers. Finally, we report in this project that caloric restriction reduces the number and size of breast cancers induced in rats exposure to chemical carcinogens.